PROJECT SUMMARY Optic neuritis is one of the most common clinical manifestations of Multiple Sclerosis (MS). It causes severe visual loss due to inflammatory demyelination of the optic nerve (ON) and subsequent degeneration of ON and retinal ganglion cells (RGCs). The significant unmet clinical need for neuroprotectants is due to the lack of understanding of the key upstream signals that trigger the neurodegenerative cascade. Our previous studies demonstrated that both acute and chronic ON injury induce endoplasmic reticulum (ER) stress in RGCs. We were able to protect the injured RGC soma and axons if we blocked the detrimental effects of ER stress by manipulating two key downstream molecules of the unfolded protein response (UPR) in opposite ways: a) deletion of CCAAT/enhancer binding protein homologous protein (CHOP), and/or b) activation of X-box binding protein 1 (XBP-1). Thus axon injury-induced ER stress may be a common mechanism of neuronal damage and targeting neuronal ER stress may have considerable therapeutic neuroprotective potential in diseases associated with axonopathy. The rodent experimental autoimmune encephalomyelitis (EAE) model induced by immunization with myelin proteins replicates many clinical symptoms and pathological signs of MS, including optic neuritis and significant RGC soma and axon loss. ER stress has been detected in white and grey matter of MS patients' brains and in EAE mice. We confirmed the role of neuronal ER stress in autoimmune-induced neurodegeneration in EAE. Furthermore, exciting recent studies of axonal Wallerian degeneration have shown that several key molecules involved in axonal NAD+ metabolism are critical for axonal degeneration. SARM1 (Sterile Alpha and TIR Motif 1), for example, is negatively regulated by axonal NAD+ synthetic enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) to induce axon degeneration; deletion of SARM1 or activation of axonal NMNATs results in axon protection. Here we propose to test the hypothesis that modulating both intrinsic neuronal ER stress and NAD+ metabolism will synergistically prevent both RGC soma and axon (ON) degeneration and preserve vision in EAE/optic neuritis. We anticipate that this study will unambiguously identify novel therapeutic targets and that our findings will ultimately be translated safely into innovative neuroprotective treatments for patients with MS and optic neuritis.